The expected rapid increase in the prevalence of Alzheimer's disease (AD) will have a significant impact on the economic and social structure of this country and as a result, there is a critical need for research focusing on developing early intervention and prevention strategies. One approach to developing primary prevention strategies for AD is to study cognitive and neurobiological changes occurring in middle-aged individuals who do not have dementia but may be at increased risk for developing the disease. One such group is the adult children of persons with AD who are at increased risk of developing the disease due to heredity, environmental and health risk factors shared with affected parents. The University of Wisconsin is prepared to conduct such a study because of the existence of the Wisconsin Registry for Alzheimer's Prevention (WRAP). WRAP focuses specifically on adult children of persons with AD in an effort to facilitate early detection and develop strategies to reduce the risk of developing AD. To date, we have archived DMA, plasma and serum samples and conducted extensive assessments on over 825 adult children of persons with AD and control subjects without a family history. The purpose of this prospective cohort study is to conduct a second wave of laboratory and neuropsychological testing and structural and functional MRI in order to define patterns and predictors of cognitive change over a 4-year re-test interval. Our long term goal is to identify health and lifestyle variables associated with abnormal cognitive aging and the development of AD and to use this information to develop interventions that will prevent or delay the onset of the disease. Our overall hypothesis is that adult children of persons with AD will exhibit signs of abnormal cognitive aging with declines in learning, memory and executive function and volumetric and fMRI abnormalities that will be predicted by specific genetic, vascular and lifestyle risk factors for AD. The Specific Aims are: 1) determine the differential effects of family history of AD and apolipoprotein (APOE) 4 allele on the cognitive aging of participants; 2) determine the effects of vascular and lifestyle risk factors on the cognitive aging of participants; and 3) examine the differential effect of family history of AD and the APOE 4 allele on brain aging as determined by rates of longitudinal decline in brain volume and fMRI activation during episodic memory tests that are known to activate regions of the brain affected by AD.